New and Rare<i>GJB2</i>Alleles in Patients with Nonsyndromic Sensorineural Hearing Impairment: A Genotype/Auditory Phenotype Correlation

Stanghellini, Ilaria; Genovese, Elisabetta; Palma, Silvia; Ravani, Anna; Falcinelli, Cristina; Guarnaccia, Maria C.

doi:10.1089/gtmb.2014.0185

Cited by 5 publications

(4 citation statements)

References 23 publications

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“…It was first reported in three Spanish siblings who were compound heterozygous for c.-22-2A>C and c.35delG, and presented with mild postlingual HI (Gandía et al, 2013 ). Later on, this same genotype was reported in an Italian subject with moderate HI (Stanghellini et al, 2014 ). The effects of the mutation were investigated by RT-PCR on RNA extracted from saliva from one of the siblings of the Spanish family.…”

Section: Genetic Alterations That Results In Dfnb1 Hearing Impairmentsupporting

confidence: 67%

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Castillo

2017

Front. Mol. Neurosci.

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The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI), GJB2, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph. GJB2 lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the GJB2 gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the GJB2 gene or remove a regulatory element essential for GJB2 expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the GJB2 coding sequence. We focus on how these alterations disrupt GJB2 and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.

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Section: Genetic Alterations That Results In Dfnb1 Hearing Impairmentsupporting

confidence: 67%

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Castillo

2017

Front. Mol. Neurosci.

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“…2b). The c.-22-2A>C variant leads to mild post-lingual HI when homozygous, which may go undiagnosed, and was previously only described in three siblings in Spain [27] and one proband in Italy [28], but has, to our knowledge, never been reported in an Ashkenazi Jewish HI patient.…”

Section: Discussionmentioning

confidence: 68%

Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

Chakchouk

Zhang

et al. 2019

Eur J Hum Genet

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Hearing impairment (HI) is characterized by extensive genetic heterogeneity. To determine the population-specific contribution of known autosomal recessive nonsyndromic (ARNS)HI genes and variants to HI etiology; pathogenic and likely pathogenic (PLP) ARNSHI variants were selected from ClinVar and the Deafness Variation Database and their frequencies were obtained from gnomAD for seven populations. ARNSHI prevalence due to PLP variants varies greatly by population ranging from 96.9 affected per 100,000 individuals for Ashkenazi Jews to 5.2 affected per 100,000 individuals for Africans/African Americans. For Europeans, Finns have the lowest prevalence due to ARNSHI PLP variants with 9.5 affected per 100,000 individuals. For East Asians, Latinos, non-Finish Europeans, and South Asians, ARNSHI prevalence due to PLP variants ranges from 17.1 to 33.7 affected per 100,000 individuals. ARNSHI variants that were previously reported in a single ancestry or family were observed in additional populations, e.g., USH1C p.(Q723*) reported in a Chinese family was the most prevalent pathogenic variant observed in gnomAD for African/African Americans. Variability between populations is due to how extensively ARNSHI has been studied, ARNSHI prevalence and ancestry specific ARNSHI variant architecture which is impacted by population history. Our study demonstrates that additional gene and variant discovery studies are necessary for all populations and particularly for individuals of African ancestry.

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“…Therefore, we recommend a target examination of this area with Sanger sequencing. It should be used specifically for GJB2 patients with a heterozygous pathogenic GJB2 variant and before the NGS of other hearing-loss genes is performed [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

The Cause of Hereditary Hearing Loss in GJB2 Heterozygotes—A Comprehensive Study of the GJB2/DFNB1 Region

Brožková

Meszarosova

Laššuthová

et al. 2021

Genes

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Hearing loss is a genetically heterogeneous sensory defect, and the frequent causes are biallelic pathogenic variants in the GJB2 gene. However, patients carrying only one heterozygous pathogenic (monoallelic) GJB2 variant represent a long-lasting diagnostic problem. Interestingly, previous results showed that individuals with a heterozygous pathogenic GJB2 variant are two times more prevalent among those with hearing loss compared to normal-hearing individuals. This excess among patients led us to hypothesize that there could be another pathogenic variant in the GJB2 region/DFNB1 locus. A hitherto undiscovered variant could, in part, explain the cause of hearing loss in patients and would mean reclassifying them as patients with GJB2 biallelic pathogenic variants. In order to detect an unknown causal variant, we examined 28 patients using NGS with probes that continuously cover the 0.4 Mb in the DFNB1 region. An additional 49 patients were examined by WES to uncover only carriers. We did not reveal a second pathogenic variant in the DFNB1 region. However, in 19% of the WES-examined patients, the cause of hearing loss was found to be in genes other than the GJB2. We present evidence to show that a substantial number of patients are carriers of the GJB2 pathogenic variant, albeit only by chance.

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New and RareGJB2Alleles in Patients with Nonsyndromic Sensorineural Hearing Impairment: A Genotype/Auditory Phenotype Correlation

Abstract: Based on patients' phenotype, reported frequency, and in silico prediction analysis, we suggest the prognostic value of eight rare and new GJB2 alleles, which may be of help to the clinician in counseling patients who carry such variants.

Cited by 5 publications

References 23 publications

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

The Cause of Hereditary Hearing Loss in GJB2 Heterozygotes—A Comprehensive Study of the GJB2/DFNB1 Region

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